1. Field
The present invention relates to pharmaceutical compositions comprising at least one lipase inhibitor.
2. Description
Lipase inhibitors include lipstatin and orlistat. The latter is also known as tetrahydrolipstatin or THL and is derived from a natural product excreted by Streptomyces toxytricini. This class of compounds was found to exhibit in vitro as well as in vivo activity against various lipases, such as lingual lipase, pancreatic lipase, gastric lipase, and carboxylester lipase. Its use for the control or prevention of obesity and hyperlipidemia is described, for instance, in U.S. Pat. No. 4,598,089.
Orlistat is currently administered at doses of 120 mg per meal and dosing is independent of the body mass of the human subject. Orlistat acts locally in the gastrointestinal (GI) tract and prevents lipase from digesting triglycerides and subsequently inhibits the formation of absorbable lipid degradation products. For this reason, systemic availability of the lipase inhibitors is not required; instead, local residence in the gastrointestinal tract is preferred.
Lipase inhibitor compositions currently administered inhibit around 30% of fat absorption after consumption of a mixed meal; an increase of the lipase inhibitors concentration in the pharmaceutical composition does not increase its clinical efficacy and/or potency while the intensity of local side effects increases.
Anal leakage of oil (oily spotting) is an adverse effect occasionally observed in patients treated with lipase inhibitors. This phenomenon reflects the physical separation of liquid unabsorbed dietary fat from the bulk of solids in the lower large intestine.
There has been a long felt need for a solution to the problem of providing lipase inhibitor compositions that improve clinical efficacy and/or potency of the inhibitor itself and/or minimize or suppress the above-mentioned disadvantages. The present invention addresses this need.
The subject invention provides a pharmaceutical composition comprising at least one lipase inhibitor and at least one fatty acid ester of a polyol. The fatty acid ester of a polyol has a melting point above body temperature and the polyol is chosen from the group consisting of glycerol, sugars, sugar derivatives, and mixtures of sugars and sugar derivatives. Preferably, the polyol is selected from the group consisting of sucrose, glycerol, and sugar alcohols, and is more preferably glycerol.
A favored fatty acid ester of a polyol is a glyceride ester, where the glyceride moiety is chosen from the group consisting of one or more triglycerides, one or more monoglycerides, one or more phospholipids, and mixtures thereof. The fatty acid moieties in the fatty acid ester of the polyol typically have, independently from each other, twelve or more carbon atoms, for example, twelve to twenty carbon atoms. Favorably, the fatty acid moiety in the fatty acid ester of the polyol is saturated
Favored polyols are triglycerides chosen from the group consisting of trilaurin, trimyristin, tripalmitin, tristearin, and mixtures thereof, and more favorably trimyristin, trilaurin, or a mixture thereof. Preferred monoglycerides are chosen from the group consisting of monocaprin, monolaurin, monomyristin, monopalmitin, and mixtures thereof. A preferred glyceride ester is an ester of a phospholipid that is a lecithin, such as a non-, partially or fully hydrogenated lecithin, or a mixture thereof. Favored lecithins include natural lecithin, synthetic lecithin, soya lecithin, egg lecithin, synthetic dipalmitoyllecithin, partially or fully hydrogenated lecithin, and mixtures thereof.
In a preferred embodiment, the at least one fatty acid ester of a polyol is present in an amount varying between 0.5% and 90% of the total weight of the composition, and further comprises at least one pharmaceutically acceptable excipient. Excipients are generally selected from the group consisting of carbohydrates, starch, starch derivatives, maltodextrines, cellulose, celluose derivatives, sugars, fillers, disintegrants, effervescents, antioxidants, anionic surfactants, nonionic surfactants, and mixtures thereof. A favored excipient is a surfactant selected from the group consisting of sodium dodecylsulfate, fatty acid salts, polyoxyethylene alkyl esters and polyoxyethylene alkyl ethers, and mixtures thereof. Other suitable excipients are selected from the group consisting of glucose, lactose, sorbitol, maltodextrin, talcum, magnesium stearate, mannitol, sodium bicarbonate, Crospovidone, glycofurol, tartaric acid, and mixtures thereof.
A desirable lipase inhibitor is an inhibitor of a gastrointestinal lipase, such as orlistat. This lipase inhibitor is typically present in an amount between 1% and 50% of the total weight of the composition, and favorably between 5% and 30% of the total weight of the composition. Preferred compositions comprise at least one lipase inhibitor that forms from 1% to 50% of the total weight of the composition, and at least one fatty acid ester of a polyol that forms from 0.5% to 90% of the total weight of the composition. Such composition may further comprise one or more pharmaceutically acceptable excipient(s).
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The subject invention provides a pharmaceutical composition comprising at least one inhibitor of lipases and at least one fatty acid ester of polyols, characterized in that the fatty acid ester has a melting point above the body temperature, e.g.,  greater than 37xc2x0 C., and the polyols are chosen from the group consisting of glycerol, sugars, sugar derivatives, and mixtures thereof.
It has surprisingly been found that administering a lipase inhibitor in a composition comprising at least one of the above fatty acid esters improves the efficacy and potency of the lipase inhibitor itself. Furthermore, inter-subject variability in efficacy and/or potency is reduced, as is the frequency and intensity of side effects.
The pharmaceutical compositions according to the present invention have been found to exhibit very favorable effects when applied orally during meal intake in humans, including an increased efficacy and potency compared to the already known compositions. This was unexpected because the compositions according to the invention are solid within the body and therefore it was expected that they should be poorly dispersed among the dietary oil particles in the stomach.
Furthermore, the inventive compositions reduce the unpleasant side effects in the single meal test compared to known compositions, despite a greater amount of fat remaining unabsorbed. During the single meal studies with human subjects, it was observed that stools obtained after intake of compositions according to the present invention show less separation of oil from the main stool mass as compared to conventional formulations. This was unexpected because equal or higher amounts of fat were present in the collected stools.
According to the present invention, the terms xe2x80x9cinhibitor of lipasesxe2x80x9d and xe2x80x9clipase inhibitorxe2x80x9d refer to compounds that are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases. Orlistat and lipstatin as described in U.S. Pat. No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin. Other lipase inhibitors include a class of compound commonly referred to as panclicins, analogues of orlistat [Mutoh et al, J. Antibiot., 47(12):1369-1375 (1994)]. The term xe2x80x9clipase inhibitorxe2x80x9d refers also to polymer bound lipase inhibitors for example described in International Patent Application W099/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterised in that they have been substituted with one or more groups that inhibit lipases. The term xe2x80x9clipase inhibitorxe2x80x9d also includes pharmaceutically acceptable salts of these compounds. The preferred xe2x80x9clipase inhibitorxe2x80x9d is orlistat.
Orlistat is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1, 1986, which also discloses processes for making orlistat and U.S. Pat. No. 6,004,996, which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described in International Patent Applications WO 00/09122 and WO 00/09123.
Orlistat is preferably orally administered from 60 to 720 mg per day in divided doses two to three times per day. Preferred is wherein from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day. The subject is preferably an obese or overweight human, e.g., a human with a body mass index of 25 or greater. Generally, it is preferred that the lipase inhibitor be administered during a meal containing fat. Generally, for administering a lipase inhibitor as defined above it is preferred that treatment be administered to a human who has a strong family history of obesity and has obtained a body mass index of 25 or greater.
The polyols can be chosen, independently from each other, from the group consisting of glycerol, sugars, sugar derivatives and mixtures of sugars and sugar derivatives. This group especially comprises sucrose, glycerol, and sugar alcohols, and most preferably glycerol, i.e. most preferably glyceride esters are used in the compositions according to the present invention.
The term xe2x80x9csugar alcoholsxe2x80x9d refer to compounds comprising mono-, oligo- and polysaccarides and their reduction products, e.g. mannitol.
The term xe2x80x9cglyceride esterxe2x80x9d refers to an ester of glycerol. According to the present invention, an ester may contain one to three, preferably one or three C12 to C20 fatty acid(s) moieties per glycerol moiety or may be a phospholipid, preferably a lecithin or mixtures thereof. For example, the glyceride esters can be chosen from the group consisting of one or more triglycerides, one or more monoglycerides, one or more phospholipids and mixtures thereof. Preferably, the fatty acid moieties in the fatty acid ester of the polyols have, independently from each other, twelve or more carbon atoms, preferably twelve to twenty carbon atoms. Most preferably, the fatty acid moieties in the fatty acid esters of the polyols hve twelve to twenty carbon atoms and are saturated.
In a preferred embodiment of the present invention suitable triglycerides are trilaurin, trimyristin, tripalmitin and tristearin and mixtures thereof. The most preferred triglycerides are trimyristin and trilaurin.
The monoglycerides can be chosen from the group consisting of monocaprin, monolaurin, monomyristin and monopalmitin and mixtures thereof.
In a preferred embodiment of the present invention, the phospholipid is preferably a lecithin, e.g. a non-, partially or fully hydrogenated lecithin or a mixture thereof. The term xe2x80x9clecithinxe2x80x9d in the context of this invention refers to esters formed of glycerol, two fatty acids, and a phosphorylcholine moiety. A lecithin has the following structure: 
wherein R1xe2x80x94COOxe2x80x94 and R2xe2x80x94COOxe2x80x94 are moieties derived from fatty acids as defined above.
The phospholipids, e.g. lecithins, may be chosen from the group consisting of natural lecithin, synthetic lecithin, soya lecithin, egg lecithin, synthetic dipalmitoyllecithin, partially or fully hydrogenated lecithin and mixtures thereof.
The fatty acid esters of polyols are known in the art and are commercially available.
Preferably, the glyceride ester is present in an amount varying between 0.5 and 90% of the total weight of the composition.
Advantageously, the pharmaceutical compositions of the present invention further comprise at least one pharmaceutically acceptable excipient. The additional excipient may be useful for enhancing the dispersion and distribution in the stomach. The excipient may be chosen from the group consisting of disintegrants, effervescents and mixtures thereof. Further excipients such as carbohydrates, starch and/or its derivatives, maltodextrines, sugars, fillers, antioxidants, anionic and nonionic surfactants such as sodium dodecylsulfate, fatty acid salts, e.g. Na-stearate, polyoxyethylene alkyl esters, polyoxyethylene alkyl ethers and mixtures thereof can also be added. Examples of additional excipients are glucose, lactose, sorbitol, maltodextrin, talcum, magnesium stearate, mannitol, sodium bicarbonate, crospovidone, glycofurol, tartaric acid and mixtures thereof
The invention is useful with any inhibitor of lipases, but is especially useful for inhibitors of the gastric and pancreatic lipase and, in particular, for the active compound orlistat.
According to the present invention, the lipase inhibitor is present in an amount varying from 1 to 50%, preferably from 5 to 30%, of the total weight of the composition.
In a preferred embodiment of the present invention the pharmaceutical composition as described above may comprise
a) 1 to 50% of the total weight of the composition is a lipase inhibitor;
b) 0.5 to 90% of the total weight of the composition is at least one fatty acid ester of polyols; and optionally the composition comprises one or more pharmaceutically acceptable excipient(s).
The compositions according to the present invention can be administered using conventional dosage forms such as hydroxypropylmethylcellulose (HPMC) capsules, hard gelatin capsules, starch capsules, tablets, chewable tablets and capsules, powders, pellets, granules, etc.
The present invention relates also to a process for preparing pharmaceutical compositions as described above, which process comprises mixing at least one inhibitor of lipases with at least one fatty acid ester of polyols, in the solid or molten state, wherein the fatty acid ester of polyols has a melting point above the body temperature and the polyols are chosen from the group consisting of glycerol, sugars, sugar derivatives and mixtures thereof.
A further aspect of the present invention is to provide a method for controlling or preventing obesity comprising the step of administering to a patient a pharmaceutical composition as described above.
The invention also relates to the use a composition as defined above for the preparation of a medicament for the prevention and treatment of obesity.